Use of 5-ALA fluorescence–guided surgery versus white-light conventional microsurgery for the resection of newly diagnosed glioblastomas (RESECT study): a French multicenter randomized phase III study

J Neurosurg 140:987–1000, 2024

Only one phase III prospective randomized study, published in 2006, has assessed the performance of 5-aminolevulinic acid (5-ALA) fluorescence–guided surgery (FGS) for glioblastoma resection. The aim of the RESECT study was to compare the onco-functional results associated with 5-ALA fluorescence and with white-light conventional microsurgery in patients with glioblastoma managed according to the current standards of care.

METHODS This was a phase III prospective randomized single-blinded study, involving 21 French neurosurgical centers, comparing 5-ALA FGS with white-light conventional microsurgery in patients with glioblastoma managed according to the current standards of care, including neuronavigation use and postoperative radiochemotherapy. Randomization was performed in a 1:1 ratio stratified by institution. 5-ALA (20 mg/kg) or placebo (ascorbic acid) was administered orally 3–5 hours before the incision. The primary endpoint was the rate of gross-total resection (GTR) blindly assessed by an independent committee. Patients without a confirmed pathological diagnosis of glioblastoma or with unavailable postoperative MRI studies were excluded from the per-protocol analysis.

RESULTS Between March 2013 and August 2016, a total of 171 patients were assigned to the 5-ALA fluorescence group (n = 88) or to the placebo group (n = 83). Twenty-four cases were excluded because the WHO histological criteria of grade 4 glioma were not met. The proportion of GTR was significantly higher in the 5-ALA fluorescence group (53/67, 79.1%) than in the placebo group (33/69, 47.8%; p = 0.0002). After adjustment for age, preoperative Karnofsky Performance Scale score, and tumor location, GTR was still associated with 5-ALA fluorescence (OR 4.13 [95% CI 1.94–8.79]). The mean 7-day postoperative Karnofsky Performance Scale score (≥ 80% in 49/71, 69.0% [5-ALA group]; 50/71, 70.4% [placebo group], p = 0.86) and the proportion of patients with a worsened neurological status 3 months postoperatively (9/68, 13.2% [5-ALA group]; 9/70, 12.9% [placebo group], p = 0.95) were similar between groups. Adverse events related to 5-ALA intake were rare and consisted of photosensitization in 4/87 (4.6%) patients and hepatic cytolysis in 1/87 (1.1%) patients. The 6-month PFS (70.2% [95% CI 57.7%–79.6%] and 68.4% [95% CI 55.7%–78.1%]; p =0.39) and 24-month OS (30.1% [95% CI 18.9%–42.0%] and 37.7% [95% CI 25.8%–49.5%]; p = 0.89) did not significantly differ. In multivariate analysis, GTR was an independent predictor of PFS (hazard ratio 0.56 [95% CI 0.36–0.86], p =0.008) and OS (hazard ratio 0.65 [95% CI 0.42–1.01], p = 0.05). The use of 5-ALA FGS generates a significant extra cost of 2732.36€ (95% CI 1658.40€–3794.11€).

CONCLUSIONS The authors found that 5-ALA FGS is an easy-to-use, cost-effective, and minimally time-consuming technique that safely optimizes the extent of resection in patients harboring glioblastoma amenable to a large resection.

Beyond fluorescence‑guided resection: 5‑ALA‑based glioblastoma therapies

Acta Neurochirurgica (2024) 166:163

Glioblastoma is the most common primary malignant brain tumor. Despite advances in multimodal concepts over the last decades, prognosis remains poor. Treatment of patients with glioblastoma remains a considerable challenge due to the infiltrative nature of the tumor, rapid growth rates, and tumor heterogeneity.

Standard therapy consists of maximally safe microsurgical resection followed by adjuvant radio- and chemotherapy with temozolomide. In recent years, local therapies have been extensively investigated in experimental as well as translational levels.

External stimuli-responsive therapies such as Photodynamic Therapy (PDT), Sonodynamic Therapy (SDT) and Radiodynamic Therapy (RDT) can induce cell death mechanisms via generation of reactive oxygen species (ROS) after administration of five-aminolevulinic acid (5-ALA), which induces the formation of sensitizing porphyrins within tumor tissue.

Preliminary data from clinical trials are available. The aim of this review is to summarize the status of such therapeutic approaches as an adjunct to current standard therapy in glioblastoma.

Sodium fluorescein uptake by the tumor microenvironment in human gliomas and brain metastases

J Neurosurg 140:958–967, 2024

Intravenous sodium fluorescein (SF) is increasingly used during surgery of gliomas and brain metastases to improve tumor resection. Currently, SF is believed to permeate the brain regions where the blood-brain barrier (BBB) is damaged and to accumulate in the extracellular space but not in tumor or healthy cells, making it possible to demarcate tumor margins to guide resection. By evaluating the immune contexture of a number of freshly resected gliomas and brain metastases from patients undergoing SF-guided surgery, the authors recurrently observed fluorescence-positive cells. Therefore, the aim of this study was to determine if SF accumulates inside the cells of the tumor microenvironment (TME), and if so, in which type of cells, and whether incorporation can also be observed in the leukocytes of peripheral blood.

METHODS Freshly resected tumor specimens were dissociated to single cells and analyzed by multiparametric flow cytometry. Peripheral blood leukocytes, macrophages, and a glioma cell line were treated with SF in vitro, and their cell uptake was assessed by multiparametric and imaging flow cytometry and by confocal microscopy.

RESULTS The ex vivo and in vitro analyses revealed that SF accumulates intracellularly in leukocytes as well as in tumor cells, but with a high variability of incorporation in the different cell subsets analyzed. Myeloid cells showed the highest level of fluorescence. In vitro uptake experiments showed that SF accumulation increases over time. The imaging analyses confirmed the internalization of the compound inside the cells.

CONCLUSIONS SF is not just a marker of BBB damage, but its intracellular detection suggests that it selectively accumulates intracellularly. Future efforts should target the mechanisms of its differential uptake by the different TME cell types in depth.

Minimally invasive keyhole approach for supramaximal frontal glioma resections

J Neurosurg 140:949–957, 2024

The authors aimed to review the frontal lobe’s surgical anatomy, describe their keyhole frontal lobectomy technique, and analyze the surgical results.

METHODS Patients with newly diagnosed frontal gliomas treated using a keyhole approach with supramaximal resection (SMR) from 2016 to 2022 were retrospectively reviewed. Surgeries were performed on patients asleep and awake. A human donor head was dissected to demonstrate the surgical anatomy. Kaplan-Meier curves were used for survival analysis.

RESULTS Of the 790 craniotomies performed during the study period, those in 47 patients met our inclusion criteria. The minimally invasive approach involved four steps: 1) debulking the frontal pole; 2) subpial dissection identifying the sphenoid ridge, olfactory nerve, and optic nerve; 3) medial dissection to expose the falx cerebri and interhemispheric structures; and 4) posterior dissection guided by motor mapping, avoiding crossing the inferior plane defined by the corpus callosum. A fifth step could be added for nondominant lesions by resecting the inferior frontal gyrus. Perioperative complications were recorded in 5 cases (10.6%). The average hospital length of stay was 3.3 days. High-grade gliomas had a median progression-free survival of 14.8 months and overall survival of 23.9 months.

CONCLUSIONS Keyhole approaches enabled successful SMR of frontal gliomas without added risks. Robust anatomical knowledge and meticulous surgical technique are paramount for obtaining successful resections.

Awake Versus Asleep Craniotomy for Patients With Eloquent Glioma: A Systematic Review and Meta-Analysis

Neurosurgery 94:38–52, 2024

Awake vs asleep craniotomy for patients with eloquent glioma is debatable. This systematic review and meta-analysis sought to compare awake vs asleep craniotomy for the resection of gliomas in the eloquent regions. METHODS: MEDLINE and PubMed were searched from inception to December 13, 2022. Primary outcomes were the extent of resection (EOR), overall survival (month), progression-free survival (month), and rates of neurological deficit, Karnofsky performance score, and seizure freedom at the 3-month follow-up. Secondary outcomes were duration of operation (minute) and length of hospital stay (LOS) (day).

RESULTS: Fifteen studies yielded 2032 patients, from which 800 (39.4%) and 1232 (60.6%) underwent awake and asleep craniotomy, respectively. The meta-analysis concluded that the awake group had greater EOR (mean difference [MD]= MD= 8.52 [4.28, 12.76], P < .00001), overall survival (MD = 2.86 months [1.35, 4.37], P = .0002), progression-free survival (MD = 5.69 months [0.75, 10.64], P = .02), 3-month postoperative Karnofsky performance score (MD = 13.59 [11.08, 16.09], P < .00001), and 3-month postoperative seizure freedom (odds ratio = 8.72 [3.39, 22.39], P < .00001). Furthermore, the awake group had lower 3-month postoperative neurological deficit (odds ratio = 0.47 [0.28, 0.78], P = .004) and shorter LOS (MD = -2.99 days [-5.09, -0.88], P = .005). In addition, the duration of operation was similar between the groups (MD = 37.88 minutes [-34.09, 109.86], P = .30).

CONCLUSION: Awake craniotomy for gliomas in the eloquent regions benefits EOR, survival, postoperative neurofunctional outcomes, and LOS. When feasible, the authors recommend awake craniotomy for surgical resection of gliomas in the eloquent regions.

Does waiting for surgery matter? How time from diagnostic MRI to resection affects outcomes in newly diagnosed glioblastoma

J Neurosurg 140:80–93, 2024

Maximal safe resection is the standard of care for patients presenting with lesions concerning for glioblastoma (GBM) on magnetic resonance imaging (MRI). Currently, there is no consensus on surgical urgency for patients with an excellent performance status, which complicates patient counseling and may increase patient anxiety. This study aims to assess the impact of time to surgery (TTS) on clinical and survival outcomes in patients with GBM.

METHODS This is a retrospective study of 145 consecutive patients with newly diagnosed IDH–wild-type GBM who underwent initial resection at the University of California, San Francisco, between 2014 and 2016. Patients were grouped according to the time from diagnostic MRI to surgery (i.e., TTS): ≤ 7, > 7–21, and > 21 days. Contrast-enhancing tumor volumes (CETVs) were measured using software. Initial CETV (CETV1) and preoperative CETV (CETV2) were used to evaluate tumor growth represented as percent change (ΔCETV) and specific growth rate (SPGR; % growth/day). Overall survival (OS) and progression-free survival (PFS) were measured from the date of resection and were analyzed using the Kaplan-Meier method and Cox regression analyses.

RESULTS Of the 145 patients (median TTS 10 days), 56 (39%), 53 (37%), and 36 (25%) underwent surgery ≤ 7, > 7–21, and > 21 days from initial imaging, respectively. Median OS and PFS among the study cohort were 15.5 and 10.3 months, respectively, and did not differ among the TTS groups (p = 0.81 and 0.17, respectively). Median CETV1 was 35.9, 15.7, and 10.2 cm 3 across the TTS groups, respectively (p < 0.001). Preoperative biopsy and presenting to an outside hospital emergency department were associated with an average 12.79-day increase and 9.09-day decrease in TTS, respectively. Distance from the treating facility (median 57.19 miles) did not affect TTS. In the growth cohort, TTS was associated with an average 2.21% increase in ΔCETV per day; however, there was no effect of TTS on SPGR, Karnofsky Performance Status (KPS), postoperative deficits, survival, discharge location, or hospital length of stay. Subgroup analyses did not identify any high-risk groups for which a shorter TTS may be beneficial.

CONCLUSIONS An increased TTS for patients with imaging concerning for GBM did not impact clinical outcomes, and while there was a significant association with ΔCETV, SPGR remained unaffected. However, SPGR was associated with a worse preoperative KPS, which highlights the importance of tumor growth speed over TTS. Therefore, while it is ill advised to wait an unnecessarily long time after initial imaging studies, these patients do not require urgent/emergency surgery and can seek tertiary care opinions and/or arrange for additional preoperative support/resources. Future studies are needed to explore subgroups for whom TTS may impact clinical outcomes.

Pseudoprogression versus true progression in glioblastoma: what neurosurgeons need to know

J Neurosurg 139:748–759, 2023

Management of patients with glioblastoma (GBM) is complex and involves implementing standard therapies including resection, radiation therapy, and chemotherapy, as well as novel immunotherapies and targeted small-molecule inhibitors through clinical trials and precision medicine approaches. As treatments have advanced, the radiological and clinical assessment of patients with GBM has become even more challenging and nuanced.

Advances in spatial resolution and both anatomical and physiological information that can be derived from MRI have greatly improved the noninvasive assessment of GBM before, during, and after therapy.

Identification of pseudoprogression (PsP), defined as changes concerning for tumor progression that are, in fact, transient and related to treatment response, is critical for successful patient management. These temporary changes can produce new clinical symptoms due to mass effect and edema. Differentiating this entity from true tumor progression is a major decision point in the patient’s management and prognosis.

Providers may choose to start an alternative therapy, transition to a clinical trial, consider repeat resection, or continue with the current therapy in hopes of resolution. In this review, the authors describe the invasive and noninvasive techniques neurosurgeons need to be aware of to identify PsP and facilitate surgical decision-making.

The Impact of Extent of Ablation on Survival of Patients With Newly Diagnosed Glioblastoma Treated With Laser Interstitial Thermal Therapy

Neurosurgery 93:427–435, 2023

Upfront laser interstitial thermal therapy (LITT) can be used as part of the treatment paradigm in difficult-to-access newly diagnosed glioblastoma multiforme (ndGBM) cases. The extent of ablation, though, is not routinely quantified; thus, its specific effect on patients’ oncological outcomes is unclear.

OBJECTIVE: To methodically measure the extent of ablation in the cohort of patients with ndGBM and its effect, and other treatment-related parameters, on patients’ progression-free survival (PFS) and overall survival (OS).

METHODS: A retrospective study was conducted on 56 isocitrate dehydrogenase 1/2 wild-type patients with ndGBM treated with upfront LITT between 2011 and 2021. Patient data including demographics, oncological course, and LITTassociated parameters were analyzed.

RESULTS: Patient median age was 62.3 years (31-84), and the median follow-up duration was 11.4 months. As expected, the subgroup of patients receiving full chemoradiation was found to have the most beneficial PFS and OS (n = 34). Further analysis showed that 10 of them underwent near-total ablation and had a significantly improved PFS (10.3 months) and OS (22.7 months). Notably, 84% excess ablation was detected which was not related to a higher rate of neurological deficits. Tumor volume was also found to influence PFS and OS, but it was not possible to further corroborate this finding because of low numbers.

CONCLUSION: This study presents data analysis of the largest series of ndGBM treated with upfront LITT. Near-total ablation was shown to significantly benefit patients’ PFS and OS. Importantly, it was shown to be safe, even in cases of excess ablation and therefore could be considered when using this modality to treat ndGBM.

Fiber Density and Structural Brain Connectome in Glioblastoma Are Correlated With Glioma Cell Infiltration

Neurosurgery 92:1234–1242, 2023

Glioblastoma (GBM) preferred to infiltrate into white matter (WM) beyond the recognizable tumor margin.

OBJECTIVE: To investigate whether fiber density (FD) and structural brain connectome can provide meaningful information about WM destruction and glioma cell infiltration.

METHODS: GBM cases were collected based on inclusion criteria, and baseline information and preoperative MRI results were obtained. GBM lesions were automatically segmented into necrosis, contrast-enhanced tumor, and edema areas. We obtained the FD map to compute the FD and lnFD values in each subarea and reconstructed the structural brain connectome to obtain the topological metrics in each subarea. We also divided the edema area into a nonenhanced tumor (NET) area and a normal WM area based on the contralesional lnFD value in the edema area, and computed the NET ratio.

RESULTS: Twenty-five GBM cases were included in this retrospective study. The FD/lnFD value and topological metrics (aCp, aLp, aEg, aEloc, and ar) were significantly correlated with GBM subareas, which represented the extent of WM destruction and glioma cell infiltration. The FD/lnFD values and topological parameters were correlated with the NET ratio. In particular, the lnFD value in the edema area was correlated with the NET ratio (coefficient, 0.92). Therefore, a larger lnFD value indicates more severe glioma infiltration in the edema area and suggests an extended resection for better clinical outcomes.

CONCLUSION: The FD and structural brain connectome in this study provide a new insight into glioma infiltration and a different consideration of their clinical application in neurooncology.

Strategies, considerations, and recent advancements in the development of liquid biopsy for glioblastoma

Neurosurg Focus 53 (6):E14, 2022

Glioblastoma (GBM) is a devasting primary brain tumor with less than a 5% 5-year survival. Treatment response assessment can be challenging because of inflammatory pseudoprogression that mimics true tumor progression clinically and on imaging. Developing additional noninvasive assays is critical. In this article, the authors review various biomarkers that could be used in developing liquid biopsies for GBM, along with strengths, limitations, and future applications. In addition, they present a potential liquid biopsy design based on the use of an extracellular vesicle–based liquid biopsy targeting nonneoplastic extracellular vesicles.

METHODS The authors conducted a current literature review of liquid biopsy in GBM by searching the PubMed, Scopus, and Google Scholar databases. Articles were assessed for type of biomarker, isolation methodology, analytical techniques, and clinical relevance.

RESULTS Recent work has shown that liquid biopsies of plasma, blood, and/or CSF hold promise as noninvasive clinical tools that can be used to diagnose recurrence, assess treatment response, and predict patient outcomes in GBM. Liquid biopsy in GBM has focused primarily on extracellular vesicles, cell-free tumor nucleic acids, and whole-cell isolates as focal biomarkers. GBM tumor signatures have been generated via analysis of tumor gene mutations, unique RNA expression, and metabolic and proteomic alterations. Liquid biopsies capture tumor heterogeneity, identifying alterations in GBM tumors that may be undetectable via surgical biopsy specimens. Finally, biomarker burden can be used to assess treatment response and recurrence in GBM.

CONCLUSIONS Liquid biopsy offers a promising avenue for monitoring treatment response and recurrence in GBM without invasive procedures. Although additional steps must be taken to bring liquid biopsy into the clinic, proof-of-principle studies and isolation methodologies are promising. Ultimately, CSF and/or plasma-based liquid biopsy is likely to be a powerful tool in the neurosurgeon’s arsenal in the near future for the treatment and management of GBM patients.

Early Diagnosis and Surgical Intervention Within 3 Weeks From Symptom Onset Are Associated With Prolonged Survival of Patients With Glioblastoma

Neurosurgery 91:741–748, 2022

Glioblastoma (GBM) is a rapidly growing and most life-threatening malignant brain tumor. The significance of early treatment to the clinical outcomes of patients with GBM is unclear.

OBJECTIVE: To determine whether early diagnosis and surgery improve the preoperative and postoperative Karnofsky performance status (KPS) and prognosis of patients with GBM.

METHODS: Data of isocitrate dehydrogenase-wildtype patients with GBM treated at our institution between January 2010 and December 2019 were reviewed. Patients were classified into early or late diagnosis groups with a threshold of 14 days from initial symptoms. In addition, patients were divided into early, intermediate, and late surgery groups with thresholds of 21 and 35 days. Representative symptoms and patient prognoses were examined.

RESULTS: Of 153 patients, 72 and 81 were classified into the early and late diagnosis groups. The median tumor volume was significantly smaller in the former group. The proportion of patients with preoperative KPS scores ≥ 90 was 48.6%and 29.6% in the early and late diagnosis groups (P = .016). The early, intermediate, and late surgery groups included 43, 24, and 86 patients. The median overall survival was significantly longer in the early surgery group than in the late surgery group (28.4 vs 18.7 months, P = .006). Multivariate analysis demonstrated that significant predictors of shorter survival included extent of tumor resection (partial or biopsy), preoperative and postoperative KPS ≤ 60, and O6-methylguanine-DNA-methyltransferase promoter status (unmethylated).

CONCLUSION: Early diagnosis within 2 weeks and surgical interventions within 3 weeks from the symptom onset are associated with prolonged patient survival. Early GBM treatment will benefit patients with GBM.

Laser Interstitial Thermal Therapy for First-Line Treatment of Surgically Accessible Recurrent Glioblastoma: Outcomes Compared With a Surgical Cohort

Neurosurgery 91:701–709, 2022

Laser interstitial thermal therapy (LITT) for glioblastoma (GBM) has been reserved for poor surgical candidates and deep “inoperable” lesions. We present the first reported series of LITT for surgically accessible recurrent GBM (rGBM) that would otherwise be treated with surgical resection.

OBJECTIVE: To evaluate the use of LITT for unifocal, lobar, first-time rGBM compared with a similar surgical cohort.

METHODS: A retrospective institutional database was used to identify patients with unifocal, lobar, first-time rGBM who underwent LITT or resection between 2013 and 2020. Clinical and volumetric lesional characteristics were compared between cohorts. Subgroup analysis of patients with lesions ≤20 cm 3 was also completed. Primary outcomes were overall survival and progression-free survival.

RESULTS: Of the 744 patients with rGBM treated from 2013 to 2020, a LITT cohort of 17 patients were compared with 23 similar surgical patients. There were no differences in baseline characteristics, although lesions were larger in the surgical cohort (7.54 vs 4.37 cm3 , P = .017). Despite differences in lesion size, both cohorts had similar extents of ablation/resection (90.7% vs 95.1%, P = .739). Overall survival (14.1 vs 13.8 months, P = .578) and progression-free survival (3.7 vs 3.3 months, P = 0. 495) were similar. LITT patients had significantly shorter hospital stays (2.2 vs 3.0 days, P = .004). Subgroup analysis of patients with lesions ≤20 cm 3 showed similar outcomes, with LITT allowing for significantly shorter hospital stays.

CONCLUSION: We found no difference in survival outcomes or morbidity between LITT and repeat surgery for surgically accessible rGBM while LITT resulted in shorter hospital stays and more efficient postoperative care.

 

 

Outcome of glioblastoma resection in patients 80 years of age and older

Acta Neurochirurgica (2022) 164:373–383

Objective To evaluate the role and possible complications of tumor resection in the management of glioblastoma (GBM) in a series of patients 80 years of age and older with review of literature.

Methods The authors retrospectively analyzed cases involving patients 80 years or older who underwent biopsy or initial resection of GBM at their hospital between 2007 and 2018. A total of 117 patients (mean age 82 years) met the inclusion criteria; 57 had resection (group A) and 60 had biopsy (group B). Functional outcomes and survival at follow-up were analyzed.

Results Group A differed significantly from group B at baseline in having betterWHO performance status, better ASA scores, more right-sided tumors, and no basal ganglia or “butterfly” gliomas. Nevertheless, 56% of group A patients had an ASA score of 3. Median survival was 9.5 months (95% CI 8–17 months) in group A, 4 months (95% CI 3.5–6 months) in group B, and 17.5 months (95% CI 12–24 months) in the 56% of group A patients treated with resection and Stupp protocol. Rates of postoperative neurologic and medical complications were almost identical in the 2 groups, but the rate of surgical site complications was substantially greater in group A (12% vs 5%). There was no significant difference in mean preoperative and postoperative KPS scores (group A).

Conclusions In selected patients 80 years or older, radical removal of GBM was associated with acceptable survival and a low perioperative complication rate which is comparable to that of a biopsy. Although the median survival of the whole group was lower than reported for younger patients, a subgroup amenable to radical surgery and Stupp protocol achieved a median survival of 17.5 months.

Influence of supramarginal resection on survival outcomes after gross-total resection of IDH–wild-type glioblastoma

J Neurosurg 136:1–8, 2022

The authors’ goal was to use a multicenter, observational cohort study to determine whether supramarginal resection (SMR) of FLAIR-hyperintense tumor beyond the contrast-enhanced (CE) area influences the overall survival (OS) of patients with isocitrate dehydrogenase–wild-type (IDH-wt) glioblastoma after gross-total resection (GTR).

METHODS The medical records of 888 patients aged ≥ 18 years who underwent resection of GBM between January 2011 and December 2017 were reviewed. Volumetric measurements of the CE tumor and surrounding FLAIR-hyperintense tumor were performed, clinical variables were obtained, and associations with OS were analyzed.

RESULTS In total, 101 patients with newly diagnosed IDH-wt GBM who underwent GTR of the CE tumor met the inclusion criteria. In multivariate analysis, age ≥ 65 years (HR 1.97; 95% CI 1.01–2.56; p < 0.001) and contact with the lateral ventricles (HR 1.59; 95% CI 1.13–1.78; p = 0.025) were associated with shorter OS, but preoperative Karnofsky Performance Status ≥ 70 (HR 0.47; 95% CI 0.27–0.89; p = 0.006), MGMT promotor methylation (HR 0.63; 95% CI 0.52–0.99; p = 0.044), and increased percentage of SMR (HR 0.99; 95% CI 0.98–0.99; p = 0.02) were associated with longer OS. Finally, 20% SMR was the minimum percentage associated with beneficial OS (HR 0.56; 95% CI 0.35–0.89; p = 0.01), but > 60% SMR had no significant influence (HR 0.74; 95% CI 0.45–1.21; p = 0.234).

CONCLUSIONS SMR is associated with improved OS in patients with IDH-wt GBM who undergo GTR of CE tumor. At least 20% SMR of the CE tumor was associated with beneficial OS, but greater than 60% SMR had no significant influence on OS.

“Zooming in” on Glioblastoma: Understanding Tumor Heterogeneity and its Clinical Implications in the Era of Single-Cell Ribonucleic Acid Sequencing

Neurosurgery 88:477–486, 2021

Glioblastoma (GBM) is the most common primary brain malignancy in adults and one of the most aggressive of all human cancers. It is highly recurrent and treatment-resistant, in large part due to its infiltrative nature and inter- and intratumoral heterogeneity. This heterogeneity entails varying genomic landscapes and cell types within and between tumors and the tumor microenvironment (TME). In GBM, heterogeneity is a driver of treatment resistance, recurrence, and poor prognosis, representing a substantial impediment to personalized medicine.

Over the last decade, sequencing technologies have facilitated deeper understanding of GBM heterogeneity by “zooming in” progressively further on tumor genomics and transcriptomics. Initial efforts employed bulk ribonucleic acid (RNA) sequencing, which examines composite gene expression of whole tumor specimens. While groundbreaking at the time, this bulk RNAseq masks the crucial contributions of distinct tumor subpopulations to overall gene expression. This work progressed to the use of bulk RNA sequencing in anatomically and spatially distinct tumor subsections, which demonstrated previously underappreciated genomic complexity of GBM.

A revolutionary next step forward has been the advent of single-cell RNA sequencing (scRNAseq), which examines gene expression at the single-cell level. scRNAseq has enabled us to understand GBM heterogeneity in unprecedented detail.

We review seminal studies in our progression of understanding GBM heterogeneity, with a focus on scRNAseq and the insights that it has provided into understanding the GBM tumor mass, peritumoral space, and TME. We highlight preclinical and clinical implications of this work and consider its potential to impact neuro-oncology and to improve patient outcomes via personalized medicine.

A Prospective Cohort Study of Neural Progenitor Cell-Sparing Radiation Therapy Plus Temozolomide for Newly Diagnosed PatientsWith Glioblastoma

Neurosurgery 87:E31–E40, 2020

In treating glioblastoma, irradiation of the neural progenitor cell (NPC) niches is controversial. Lower hippocampal doses may limit neurocognitive toxicity, but higher doses to the subventricular zones (SVZ) may improve survival.

OBJECTIVE: To prospectively evaluate the impact of limiting radiation dose to the NPC niches on tumor progression, survival, and cognition in patients with glioblastoma.

METHODS: Patients with glioblastoma received resection followed by standard chemoradiation. Radiation dose to the NPC niches, including the bilateral hippocampi and SVZ, was minimized without compromising tumor coverage. The primary outcome was tumor progression in the spared NPC niches. Follow-up magnetic resonance imaging was obtained bimonthly. Neurocognitive testing was performed before treatment and at 6- and 12-mo follow-up. Cox regression evaluated predictors of overall and progressionfree survival. Linear regression evaluated predictors of neurocognitive decline. RESULTS: A total of 30 patients enrolled prospectively. The median age was 58 yr. Median mean doses to the hippocampi and SVZ were 49.1 and 41.8 gray (Gy) ipsilaterally, and 16.5 and 19.9 Gy contralaterally. Median times to death and tumor progression were 16.0 and 7.6 mo, and were not significantly different compared to a matched historical control. No patients experienced tumor progression in the spared NPC-containing regions. Overall survival was associated with neurocognitive function (P ≤ .03) but not dose to the NPC niches. Higher doses to the hippocampi and SVZ predicted greater decline in verbal memory (P ≤ .01).

CONCLUSION: In treating glioblastoma, limiting dose to the NPC niches may reduce cognitive toxicity while maintaining clinical outcomes. Further studies are needed to confirm these results.

 

Characterizing tumor invasiveness of glioblastoma using multiparametric magnetic resonance imaging

J Neurosurg 132:1465–1472, 2020

The objective of this study was to characterize the abnormalities revealed by diffusion tensor imaging (DTI) using MR spectroscopy (MRS) and perfusion imaging, and to evaluate the prognostic value of a proposed quantitative measure of tumor invasiveness by combining contrast-enhancing (CE) and DTI abnormalities in patients with glioblastoma.

METHODS Eighty-four patients with glioblastoma were recruited preoperatively. DTI was decomposed into isotropic (p) and anisotropic (q) components. The relative cerebral blood volume (rCBV) was calculated from the dynamic susceptibility contrast imaging. Values of N-acetylaspartate, myoinositol, choline (Cho), lactate (Lac), and glutamate + glutamine (Glx) were measured from multivoxel MRS and normalized as ratios to creatine (Cr). Tumor regions of interest (ROIs) were manually segmented from the CE T1-weighted (CE-ROI) and DTI-q (q-ROI) maps. Perfusion and metabolic characteristics of these ROIs were measured and compared. The relative invasiveness coefficient (RIC) was calculated as a ratio of the characteristic radii of CE-ROI and q-ROI. The prognostic significance of RIC was tested using Kaplan-Meier and multivariate Cox regression analyses.

RESULTS The Cho/Cr, Lac/Cr, and Glx/Cr in q-ROI were significantly higher than CE-ROI (p = 0.004, p = 0.005, and p = 0.007, respectively). CE-ROI had significantly higher rCBV values than q-ROI (p < 0.001). A higher RIC was associated with worse survival in a multivariate overall survival (OS) model (hazard ratio [HR] 1.40, 95% confidence interval [CI] 1.06–1.85, p = 0.016) and progression-free survival (PFS) model (HR 1.55, 95% CI 1.16–2.07, p = 0.003). An RIC cutoff value of 0.89 significantly predicted shorter OS (median 384 vs 605 days, p = 0.002) and PFS (median 244 vs 406 days, p = 0.001).

CONCLUSIONS DTI-q abnormalities displayed higher tumor load and hypoxic signatures compared with CE abnormalities, whereas CE regions potentially represented the tumor proliferation edge. Integrating the extents of invasion visualized by DTI-q and CE images into clinical practice may lead to improved treatment efficacy.

Impact of Extent of Resection on Incidence of Postoperative Complications in PatientsWith Glioblastoma

Neurosurgery 86:625–630, 2020

Extent of resection (EOR) is well established as correlating with overall survival in patients with glioblastoma (GBM). The impact of EOR on reported quality metrics such as patient safety indicators (PSIs) and hospital-acquired conditions (HACs) is unknown.

OBJECTIVE: To perform a retrospective study to evaluate possible associations between EOR and the incidence of PSIs and HACs.

METHODS: We queried all patients diagnosed with GBM who underwent surgical resection at our institution between January 2011 and May 2017. Pre- and postoperative magnetic resonance imageswere analyzed for EOR. Each chart was reviewed to determine the incidence of PSIs and HACs.

RESULTS: A total of 284 patients met the inclusion criteria. EOR ranged from 39.00 to 100%, with a median of 99.84% and a mean of 95.7%. There were 16 PSI, and 13 HAC, events. There were no significant differences in the rates of PSIs or HACs when compared between patients stratified by gross total resection (EOR ≥ 95%) and subtotal resection (EOR < 95%). The odds of encountering a PSI or HAC were 2.5 times more likely in the subtotal resection group compared to the gross total resection group (P = .58). After adjusting for confounders, the odds of encountering a PSI or HAC in the subtotal resection group were 3.9 times greater than for the gross total resection group (P < .05).

CONCLUSION: Gross total resection of GBM is associated with a decreased incidence of PSIs and HACs, as compared to subtotal resection.

An Online Calculator for the Prediction of Survival in Glioblastoma Patients Using Classical Statistics and Machine Learning

Neurosurgery, Volume 86, Issue 2, February 2020, Pages E184–E192

Although survival statistics in patients with glioblastoma multiforme (GBM) are well-defined at the group level, predicting individual patient survival remains challenging because of significant variation within strata.

OBJECTIVE: To compare statistical and machine learning algorithms in their ability to predict survival in GBM patients and deploy the best performing model as an online survival calculator.

METHODS: Patients undergoing an operation for a histopathologically confirmed GBM were extracted from the Surveillance Epidemiology and End Results (SEER) database (2005-2015) and split into a training and hold-out test set in an 80/20 ratio. Fifteen statistical and machine learning algorithms were trained based on 13 demographic, socioeconomic, clinical, and radiographic features to predict overall survival, 1-yr survival status, and compute personalized survival curves.

RESULTS: In total, 20 821 patients met our inclusion criteria. The accelerated failure time model demonstrated superior performance in terms of discrimination (concordance index = 0.70), calibration, interpretability, predictive applicability, and computational efficiency compared to Cox proportional hazards regression and other machine learning algorithms. This model was deployed through a free, publicly available software interface (https://cnoc-bwh.shinyapps.io/gbmsurvivalpredictor/).

CONCLUSION: The development and deployment of survival prediction tools require a multimodal assessment rather than a single metric comparison. This study provides a framework for the development of prediction tools in cancer patients, as well as an online survival calculator for patients with GBM. Future efforts should improve the interpretability, predictive applicability, and computational efficiency of existing machine learning algorithms, increase the granularity of population-based registries, and externally validate the proposed prediction tool.

5-Aminolevulinic Acid Fluorescence-Guided Resection of 18F-FET-PET Positive Tumor Beyond Gadolinium Enhancing Tumor Improves Survival in Glioblastoma

Neurosurgery 85:E1020–E1029, 2019

The value of early postoperative 18F-FET-PET in patients with glioblastoma (GBM) is unclear. Five-aminolevulinic acid (5-ALA) is used for fluorescence-guided resections in these patients and previous data suggest that fluorescence and 18F-FET-PET both demarcate larger tumor volumes than gadolinium enhanced magnet resonance imaging (MRI).

OBJECTIVE: To correlate fluorescence with enhancing volumes on postoperative MRI and 18F-FET-PET tumor volumes, and determine the value of postoperative 18F-FET-PET for predicting survival through observational study.

METHODS: GBM patients underwent fluorescence-guided resection after administration of 5-ALA followed by early postoperative MRI and 18F-FET-PET for determination of residual tissue volumes. All patients were treated with standard temozolomide radiochemotherapy and monitored for progression-free and overall survival (PFS, OS).

RESULTS: A total of 31 patients were included. For functional reasons, residual 5-ALA derived fluorescent tissue was left unresected in 18 patients with a median 18F-FETPET volume of 17.82 cm3 (interquartile range 6.50-29.19). In patients without residual fluorescence, median 18F-FET-PET volume was 1.20 cm3 (interquartile range 0.87-5.50) and complete resection of gadolinium enhancing tumor was observed in 100% of patients. A 18F-FET-PET volume of above 4.3 cm3 was associated with worse OS (logrank P-value≤.05), also in patients with no residual contrast enhancing tumor on MRI. More patients in whom fluorescencing tissue had been removed completely had postoperative 18F-FET-PET tumor volumes below 4.3 cm3.

CONCLUSION: Postoperative 18F-FET-PET volumes predict OS and PFS. Resection of 5-ALA derived fluorescence beyond gadolinium enhancing tumor tissue leads to lower postoperative 18F-FET-PET tumor volumes and improved OS and PFS without additional deficits.